European Approval Sought for Adagrasib in Previously Treated KRAS G12C–Mutated NSCLC

A marketing authorization application has been submitted to the European Medicines Agency seeking the approval of adagrasib for therapeutic use in previously treated patients with non–small cell lung cancer harboring a KRAS G12C mutation.

A marketing authorization application has been submitted to the European Medicines Agency (EMA) seeking the approval of adagrasib for therapeutic use in previously treated patients with non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation.1

The application is supported by findings from the phase 2 KRYSTAL-1 trial (NCT03785249). At a median follow-up of 9 months, patients with KRAS G12C–mutated NSCLC who received 600 mg of adagrasib twice daily achieved an objective response rate (ORR) of 43% and a disease control rate of 80%, per independent central review.2

Additionally, 98.3% of patients who were administered adagrasib received prior chemotherapy and immunotherapy. Findings regarding safety and tolerability were consistent with previously reported findings with the agent in patients with advanced NSCLC.

“The submission of our application to the EMA is a significant milestone for Mirati and brings us closer to expanding the potential availability of adagrasib to patients with KRAS G12C–mutated lung cancer in the European Union, if approved,” Charles Baum, MD, PhD, president, founder and head of Research and Development at Mirati Therapeutics, Inc., stated in a press release. “Therapeutic options for KRAS G12C–mutated lung cancer are limited, and this submission is an important step forward in our goal to deliver innovative, differentiated therapies in areas of high unmet need.”

KRYSTAL-1 aimed to enroll up to 565 patients with solid tumors harboring a KRAS G12C mutation, with unresectable or metastatic disease, who do not have available treatment with curative intent or available standard-of-care options.3

A twice-daily dose of 600 mg of adagrasib was established as the recommended phase 2 dose (RP2D) during the phase 1 dose-escalation portion of KRYSTAL-1, which also examined once-daily doses of 150 mg, 300 mg, 600 mg, and 1200 mg of adagrasib.

Phase 1 had primary end points of evaluating safety, maximum-tolerated dose, pharmacokinetics, and the RP2D. Secondary end points included ORR per RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

At a data cutoff of June 15, 2021, findings from phase 1/1b of KRYSTAL-1 demonstrated that 19 patients with KRAS G12C–mutated NSCLC who received the RP2D achieved an ORR of 58% with a median DOR of 12.6 months at a median follow-up of 17.3 months and a median duration of treatment of 9.5 months. Additionally, the median PFS was 8.3 months, and the median OS was not reached.

In phase 2 of the trial, single-agent adagrasib was evaluated in a cohort of patients with KRAS G12C–mutated NSCLC, plus cohorts of patients with colorectal cancer, solid tumors, and treatment-naïve patients with KRAS G12C– and STK11-mutated NSCLC.

Detailed results from phase 2 of the KRYSTAL-1 trial will be presented in June at the 2022 ASCO Annual Meeting.

“We look forward to working with the EMA to potentially bring this therapy to patients,” Baum said. “We also thank the patients and investigators who make our work possible by participating in clinical trials."

In February 2022, the FDA accepted a new drug application for the use of adagrasib in the treatment of patients with KRAS G12C–mutated NSCLC who received at least 1 prior systemic therapy.4

References

  1. Mirati Therapeutics submits marketing authorization application to the European Medicines Agency for investigational adagrasib as a treatment for previously-treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics. May 19, 2022. Accessed May 20, 2022. https://prn.to/3lMStoN
  2. Mirati Therapeutics announces positive phase 2 topline results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Mirati Therapeutics. September 20, 2021. Accessed May 20, 2022. https://bit.ly/3HWGZYY
  3. Weiss J, Yaeger RD, Johnson ML, et al. KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Onc. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
  4. US Food and Drug Administration (FDA) accepts Mirati Therapeutics’ new drug application for adagrasib as treatment of previously treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics. February 15, 2022. Accessed May 20, 2022. https://prn.to/3HWi0oJ